TY  - JOUR
AU  - Vastagh, Csaba
AU  - Schwirtlich, Marija
AU  - Kwakowsky, Andrea
AU  - Erdelyi, Ferenc
AU  - Margolis, Frank L.
AU  - Yanagawa, Yuchio
AU  - Katarova, Zoya
AU  - Szabo, Gabor
PY  - 2015
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/898
AB  - Gamma-aminobutyric acid (GABA) has a dual role as an inhibitory neurotransmitter in the adult central nervous system (CNS) and as a signaling molecule exerting largely excitatory actions during development. The rate-limiting step of GABA synthesis is catalyzed by two glutamic acid decarboxylase isoforms GAD65 and GAD67 coexpressed in the GABAergic neurons of the CNS. Here we report that the two GADs show virtually nonoverlapping expression patterns consistent with distinct roles in the developing peripheral olfactory system. GAD65 is expressed exclusively in undifferentiated neuronal progenitors confined to the proliferative zones of the sensory vomeronasal and olfactory epithelia In contrast GAD67 is expressed in a subregion of the nonsensory epithelium/vomeronasal organ epithelium containing the putative Gonadotropin-releasing hormone (GnRH) progenitors and GnRH neurons migrating from this region through the frontonasal mesenchyme into the basal forebrain. Only GAD67+, but not GAD65+ cells accumulate detectable GABA. We further demonstrate that GAD67 and its embryonic splice variant embryonic GAD (EGAD) concomitant with GnRH are dynamically regulated during GnRH neuronal migration in vivo and in two immortalized cell lines representing migratory (GN11) and postmigratory (GT1-7) stage GnRH neurons, respectively. Analysis of GAD65/67 single and double knock-out embryos revealed that the two GADs play complementary (inhibitory) roles in GnRH migration ultimately modulating the speed and/or direction of GnRH migration. Our results also suggest that GAD65 and GAD67/EGAD characterized by distinct subcellular localization and kinetics have disparate functions during olfactory system development mediating proliferative and migratory responses putatively through specific subcellular GABA pools.
PB  - Wiley, Hoboken
T2  - Developmental Neurobiology
T1  - The Spatiotemporal Segregation of GAD Forms Defines Distinct GABA Signaling Functions in the Developing Mouse Olfactory System and Provides Novel Insights into the Origin and Migration of GnRH Neurons
EP  - 270
IS  - 3
SP  - 249
VL  - 75
DO  - 10.1002/dneu.22222
ER  - 

@article{
author = "Vastagh, Csaba and Schwirtlich, Marija and Kwakowsky, Andrea and Erdelyi, Ferenc and Margolis, Frank L. and Yanagawa, Yuchio and Katarova, Zoya and Szabo, Gabor",
year = "2015",
abstract = "Gamma-aminobutyric acid (GABA) has a dual role as an inhibitory neurotransmitter in the adult central nervous system (CNS) and as a signaling molecule exerting largely excitatory actions during development. The rate-limiting step of GABA synthesis is catalyzed by two glutamic acid decarboxylase isoforms GAD65 and GAD67 coexpressed in the GABAergic neurons of the CNS. Here we report that the two GADs show virtually nonoverlapping expression patterns consistent with distinct roles in the developing peripheral olfactory system. GAD65 is expressed exclusively in undifferentiated neuronal progenitors confined to the proliferative zones of the sensory vomeronasal and olfactory epithelia In contrast GAD67 is expressed in a subregion of the nonsensory epithelium/vomeronasal organ epithelium containing the putative Gonadotropin-releasing hormone (GnRH) progenitors and GnRH neurons migrating from this region through the frontonasal mesenchyme into the basal forebrain. Only GAD67+, but not GAD65+ cells accumulate detectable GABA. We further demonstrate that GAD67 and its embryonic splice variant embryonic GAD (EGAD) concomitant with GnRH are dynamically regulated during GnRH neuronal migration in vivo and in two immortalized cell lines representing migratory (GN11) and postmigratory (GT1-7) stage GnRH neurons, respectively. Analysis of GAD65/67 single and double knock-out embryos revealed that the two GADs play complementary (inhibitory) roles in GnRH migration ultimately modulating the speed and/or direction of GnRH migration. Our results also suggest that GAD65 and GAD67/EGAD characterized by distinct subcellular localization and kinetics have disparate functions during olfactory system development mediating proliferative and migratory responses putatively through specific subcellular GABA pools.",
publisher = "Wiley, Hoboken",
journal = "Developmental Neurobiology",
title = "The Spatiotemporal Segregation of GAD Forms Defines Distinct GABA Signaling Functions in the Developing Mouse Olfactory System and Provides Novel Insights into the Origin and Migration of GnRH Neurons",
pages = "270-249",
number = "3",
volume = "75",
doi = "10.1002/dneu.22222"
}

Vastagh, C., Schwirtlich, M., Kwakowsky, A., Erdelyi, F., Margolis, F. L., Yanagawa, Y., Katarova, Z.,& Szabo, G.. (2015). The Spatiotemporal Segregation of GAD Forms Defines Distinct GABA Signaling Functions in the Developing Mouse Olfactory System and Provides Novel Insights into the Origin and Migration of GnRH Neurons. in Developmental Neurobiology
Wiley, Hoboken., 75(3), 249-270.
https://doi.org/10.1002/dneu.22222

Vastagh C, Schwirtlich M, Kwakowsky A, Erdelyi F, Margolis FL, Yanagawa Y, Katarova Z, Szabo G. The Spatiotemporal Segregation of GAD Forms Defines Distinct GABA Signaling Functions in the Developing Mouse Olfactory System and Provides Novel Insights into the Origin and Migration of GnRH Neurons. in Developmental Neurobiology. 2015;75(3):249-270.
doi:10.1002/dneu.22222 .

Vastagh, Csaba, Schwirtlich, Marija, Kwakowsky, Andrea, Erdelyi, Ferenc, Margolis, Frank L., Yanagawa, Yuchio, Katarova, Zoya, Szabo, Gabor, "The Spatiotemporal Segregation of GAD Forms Defines Distinct GABA Signaling Functions in the Developing Mouse Olfactory System and Provides Novel Insights into the Origin and Migration of GnRH Neurons" in Developmental Neurobiology, 75, no. 3 (2015):249-270,
https://doi.org/10.1002/dneu.22222 . .

TY  - JOUR
AU  - Schwirtlich, Marija
AU  - Kwakowsky, Andrea
AU  - Emri, Zsuzsa
AU  - Antal, Karoly
AU  - Lacza, Zsombor
AU  - Cselenyak, Attila
AU  - Katarova, Zoya
AU  - Szabo, Gabor
PY  - 2011
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/490
AB  - Primary lens epithelial cell (LEC) cultures derived from newborn (P0) and one-month-old (P30) mouse lenses were used to study GABA (gamma-aminobutyric acid) signaling expression and its effect on the intracellular Ca2+ ([Ca2+](i)) level. We have found that these cultures express specific cellular markers for lens epithelial and fiber cells, all components of the functional GABA signaling pathway and GABA, thus recapitulating the developmental program of the ocular lens. Activation of both GABA-A and GABA-B receptors (GABA(A)R and GABA(B)R) with the specific agonists muscimol and baclofen, respectively induces [Ca2+](i) transients that could be blocked by the specific antagonists bicuculline and CGP55845 and were dependent on extracellular Ca2+. Bicuculline did not change the GABA-evoked Ca2+ responses in Ca-2-containing buffers, but suppressed them significantly in Ca2+-free buffers suggesting the two receptors couple to convergent Ca2+ mobilization mechanisms with different extracellular Ca2+ sensitivity. Prolonged activation of GABA(B)R induced wave propagation of the Ca2+ signal and persistent oscillations. The number of cells reacting to GABA or GABA + bicuculline in P30 mouse LEC cultures expressing predominantly the synaptic type GABA(A)R did not differ significantly from the number of reacting cells in PO mouse LEC cultures. The GABA-induced Ca2+ transients in P30 (but not P0) mouse LEC could be entirely suppressed by co-application of bicuculline and CGP55845. The GABA-mediated Ca2+ signaling may be involved in a variety of Ca2+-dependent cellular processes during lens growth and epithelial cell differentiation.
PB  - Elsevier Sci Ltd, Oxford
T2  - Cell Calcium
T1  - GABAergic signaling in primary lens epithelial and lentoid cells and its involvement in intracellular Ca2+ modulation
EP  - 392
IS  - 4
SP  - 381
VL  - 50
DO  - 10.1016/j.ceca.2011.07.002
ER  - 

@article{
author = "Schwirtlich, Marija and Kwakowsky, Andrea and Emri, Zsuzsa and Antal, Karoly and Lacza, Zsombor and Cselenyak, Attila and Katarova, Zoya and Szabo, Gabor",
year = "2011",
abstract = "Primary lens epithelial cell (LEC) cultures derived from newborn (P0) and one-month-old (P30) mouse lenses were used to study GABA (gamma-aminobutyric acid) signaling expression and its effect on the intracellular Ca2+ ([Ca2+](i)) level. We have found that these cultures express specific cellular markers for lens epithelial and fiber cells, all components of the functional GABA signaling pathway and GABA, thus recapitulating the developmental program of the ocular lens. Activation of both GABA-A and GABA-B receptors (GABA(A)R and GABA(B)R) with the specific agonists muscimol and baclofen, respectively induces [Ca2+](i) transients that could be blocked by the specific antagonists bicuculline and CGP55845 and were dependent on extracellular Ca2+. Bicuculline did not change the GABA-evoked Ca2+ responses in Ca-2-containing buffers, but suppressed them significantly in Ca2+-free buffers suggesting the two receptors couple to convergent Ca2+ mobilization mechanisms with different extracellular Ca2+ sensitivity. Prolonged activation of GABA(B)R induced wave propagation of the Ca2+ signal and persistent oscillations. The number of cells reacting to GABA or GABA + bicuculline in P30 mouse LEC cultures expressing predominantly the synaptic type GABA(A)R did not differ significantly from the number of reacting cells in PO mouse LEC cultures. The GABA-induced Ca2+ transients in P30 (but not P0) mouse LEC could be entirely suppressed by co-application of bicuculline and CGP55845. The GABA-mediated Ca2+ signaling may be involved in a variety of Ca2+-dependent cellular processes during lens growth and epithelial cell differentiation.",
publisher = "Elsevier Sci Ltd, Oxford",
journal = "Cell Calcium",
title = "GABAergic signaling in primary lens epithelial and lentoid cells and its involvement in intracellular Ca2+ modulation",
pages = "392-381",
number = "4",
volume = "50",
doi = "10.1016/j.ceca.2011.07.002"
}

Schwirtlich, M., Kwakowsky, A., Emri, Z., Antal, K., Lacza, Z., Cselenyak, A., Katarova, Z.,& Szabo, G.. (2011). GABAergic signaling in primary lens epithelial and lentoid cells and its involvement in intracellular Ca2+ modulation. in Cell Calcium
Elsevier Sci Ltd, Oxford., 50(4), 381-392.
https://doi.org/10.1016/j.ceca.2011.07.002

Schwirtlich M, Kwakowsky A, Emri Z, Antal K, Lacza Z, Cselenyak A, Katarova Z, Szabo G. GABAergic signaling in primary lens epithelial and lentoid cells and its involvement in intracellular Ca2+ modulation. in Cell Calcium. 2011;50(4):381-392.
doi:10.1016/j.ceca.2011.07.002 .

Schwirtlich, Marija, Kwakowsky, Andrea, Emri, Zsuzsa, Antal, Karoly, Lacza, Zsombor, Cselenyak, Attila, Katarova, Zoya, Szabo, Gabor, "GABAergic signaling in primary lens epithelial and lentoid cells and its involvement in intracellular Ca2+ modulation" in Cell Calcium, 50, no. 4 (2011):381-392,
https://doi.org/10.1016/j.ceca.2011.07.002 . .

TY  - JOUR
AU  - Schwirtlich, Marija
AU  - Emri, Zsuzsa
AU  - Antal, Karoly
AU  - Mate, Zoltan
AU  - Katarova, Zoya
AU  - Szabo, Gabor
PY  - 2010
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/420
AB  - Gamma-amminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system of vertebrates, serves as an autocrine/paracrine signaling molecule during development, modulating a number of calcium (Ca2+)-dependent processes, including proliferation, migration, and differentiation, acting via 2 types of GABA receptors (GABARs): ionotropic GABA(A)Rs and metabotropic GABA(B)Rs. Here, we demonstrate that mouse embryonic stem cells (mESCs), which possess the capacity for virtually unlimited self-renewal and pluripotency, synthesize GABA and express functional GABA(A)Rs and GABA(B)Rs, as well as voltage-gated calcium channels (VGCCs), ryanodine receptors (RyRs), and inwardly rectifying potassium (GIRK) channels. On activation, both GABAR types triggered synergistically intracellular calcium rise. Muscimol (a GABA(A)R agonist) induced single Ca2+ transients involving both VGCC-mediated Ca2+ influx and intracellular stores, while baclofen (a GABA(B)R agonist) evoked Ca2+ transients followed by intercellular Ca2+ waves and oscillations that were resistant to antagonists and entirely dependent on Ca2+ release from intracellular stores. Prolonged treatment with muscimol slightly inhibited, while baclofen or SR95531 (a GABA(A)R antagonist) significantly facilitated, mESC proliferation. GABA(A)R-specific ligands also induced morphological and gene expression changes indicating a differentiation shift. Our data suggest that the interplay between GABARs and downstream (coupled) effectors differentially modulates mESC proliferation/differentiation through selective activation of second messenger signaling cascades.-Schwirtlich, M., Emri, Z., Antal, K., Mate, Z., Katarova, Z., Szabo, G. GABA(A) and GABA(B) receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca2+. FASEB J. 24, 1218-1228 (2010). www.fasebj.org
PB  - Federation Amer Soc Exp Biol, Bethesda
T2  - FASEB Journal
T1  - GABA(A) and GABA(B) receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca2+
EP  - 1228
IS  - 4
SP  - 1218
VL  - 24
DO  - 10.1096/fj.09-143586
ER  - 

@article{
author = "Schwirtlich, Marija and Emri, Zsuzsa and Antal, Karoly and Mate, Zoltan and Katarova, Zoya and Szabo, Gabor",
year = "2010",
abstract = "Gamma-amminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system of vertebrates, serves as an autocrine/paracrine signaling molecule during development, modulating a number of calcium (Ca2+)-dependent processes, including proliferation, migration, and differentiation, acting via 2 types of GABA receptors (GABARs): ionotropic GABA(A)Rs and metabotropic GABA(B)Rs. Here, we demonstrate that mouse embryonic stem cells (mESCs), which possess the capacity for virtually unlimited self-renewal and pluripotency, synthesize GABA and express functional GABA(A)Rs and GABA(B)Rs, as well as voltage-gated calcium channels (VGCCs), ryanodine receptors (RyRs), and inwardly rectifying potassium (GIRK) channels. On activation, both GABAR types triggered synergistically intracellular calcium rise. Muscimol (a GABA(A)R agonist) induced single Ca2+ transients involving both VGCC-mediated Ca2+ influx and intracellular stores, while baclofen (a GABA(B)R agonist) evoked Ca2+ transients followed by intercellular Ca2+ waves and oscillations that were resistant to antagonists and entirely dependent on Ca2+ release from intracellular stores. Prolonged treatment with muscimol slightly inhibited, while baclofen or SR95531 (a GABA(A)R antagonist) significantly facilitated, mESC proliferation. GABA(A)R-specific ligands also induced morphological and gene expression changes indicating a differentiation shift. Our data suggest that the interplay between GABARs and downstream (coupled) effectors differentially modulates mESC proliferation/differentiation through selective activation of second messenger signaling cascades.-Schwirtlich, M., Emri, Z., Antal, K., Mate, Z., Katarova, Z., Szabo, G. GABA(A) and GABA(B) receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca2+. FASEB J. 24, 1218-1228 (2010). www.fasebj.org",
publisher = "Federation Amer Soc Exp Biol, Bethesda",
journal = "FASEB Journal",
title = "GABA(A) and GABA(B) receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca2+",
pages = "1228-1218",
number = "4",
volume = "24",
doi = "10.1096/fj.09-143586"
}

Schwirtlich, M., Emri, Z., Antal, K., Mate, Z., Katarova, Z.,& Szabo, G.. (2010). GABA(A) and GABA(B) receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca2+. in FASEB Journal
Federation Amer Soc Exp Biol, Bethesda., 24(4), 1218-1228.
https://doi.org/10.1096/fj.09-143586

Schwirtlich M, Emri Z, Antal K, Mate Z, Katarova Z, Szabo G. GABA(A) and GABA(B) receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca2+. in FASEB Journal. 2010;24(4):1218-1228.
doi:10.1096/fj.09-143586 .

Schwirtlich, Marija, Emri, Zsuzsa, Antal, Karoly, Mate, Zoltan, Katarova, Zoya, Szabo, Gabor, "GABA(A) and GABA(B) receptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca2+" in FASEB Journal, 24, no. 4 (2010):1218-1228,
https://doi.org/10.1096/fj.09-143586 . .

TY  - JOUR
AU  - Kwakowsky, Andrea
AU  - Schwirtlich, Marija
AU  - Zhang, Qi
AU  - Eisenstat, David D.
AU  - Erdelyi, Ferenc
AU  - Baranyi, Maria
AU  - Katarova, Zoya D.
AU  - Szabo, Gabor
PY  - 2007
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/279
AB  - Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter of the adult nervous system and its biosynthetic enzyme glutamic acid.. decarboxylase (GAD) are abundantly expressed in the embryonic nervous system and are involved in the modulation of cell proliferation, migration, and differentiation. Here we describe for the first time the expression of GABA and embryonic and adult GAD isoforms in the developing mouse lens. We show that the GAD isoforms are sequentially induced with specific spatiotemporal profiles: GAD65 and embryonic GAD isoforms prevail in primary fibers, while GAD67 is the predominant GAD expressed in the postnatal secondary fibers. This pattern correlates well with the expression of Dlx2 and Dlx5, known as upstream regulators of GAD. GABA and GAD are most abundant at the tips of elongating fibers and are absent from organelle-free cells, suggesting their involvement is primarily in shaping of the cytoskeleton during fiber elongation stages.
PB  - Wiley-Liss, Hoboken
T2  - Developmental Dynamics
T1  - GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: Correlation with Dlx2 and Dlx5
EP  - 3544
IS  - 12
SP  - 3532
VL  - 236
DO  - 10.1002/dvdy.21361
ER  - 

@article{
author = "Kwakowsky, Andrea and Schwirtlich, Marija and Zhang, Qi and Eisenstat, David D. and Erdelyi, Ferenc and Baranyi, Maria and Katarova, Zoya D. and Szabo, Gabor",
year = "2007",
abstract = "Gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter of the adult nervous system and its biosynthetic enzyme glutamic acid.. decarboxylase (GAD) are abundantly expressed in the embryonic nervous system and are involved in the modulation of cell proliferation, migration, and differentiation. Here we describe for the first time the expression of GABA and embryonic and adult GAD isoforms in the developing mouse lens. We show that the GAD isoforms are sequentially induced with specific spatiotemporal profiles: GAD65 and embryonic GAD isoforms prevail in primary fibers, while GAD67 is the predominant GAD expressed in the postnatal secondary fibers. This pattern correlates well with the expression of Dlx2 and Dlx5, known as upstream regulators of GAD. GABA and GAD are most abundant at the tips of elongating fibers and are absent from organelle-free cells, suggesting their involvement is primarily in shaping of the cytoskeleton during fiber elongation stages.",
publisher = "Wiley-Liss, Hoboken",
journal = "Developmental Dynamics",
title = "GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: Correlation with Dlx2 and Dlx5",
pages = "3544-3532",
number = "12",
volume = "236",
doi = "10.1002/dvdy.21361"
}

Kwakowsky, A., Schwirtlich, M., Zhang, Q., Eisenstat, D. D., Erdelyi, F., Baranyi, M., Katarova, Z. D.,& Szabo, G.. (2007). GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: Correlation with Dlx2 and Dlx5. in Developmental Dynamics
Wiley-Liss, Hoboken., 236(12), 3532-3544.
https://doi.org/10.1002/dvdy.21361

Kwakowsky A, Schwirtlich M, Zhang Q, Eisenstat DD, Erdelyi F, Baranyi M, Katarova ZD, Szabo G. GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: Correlation with Dlx2 and Dlx5. in Developmental Dynamics. 2007;236(12):3532-3544.
doi:10.1002/dvdy.21361 .

Kwakowsky, Andrea, Schwirtlich, Marija, Zhang, Qi, Eisenstat, David D., Erdelyi, Ferenc, Baranyi, Maria, Katarova, Zoya D., Szabo, Gabor, "GAD isoforms exhibit distinct spatiotemporal expression patterns in the developing mouse lens: Correlation with Dlx2 and Dlx5" in Developmental Dynamics, 236, no. 12 (2007):3532-3544,
https://doi.org/10.1002/dvdy.21361 . .